Guidelines developed by the National Cholesterol Education Program's Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, as reported in Arch. Intern. Med., 148, 36 (1988), identified elevated cholesterol and low-density lipoprotein cholesterol (LDL-C) concentrations as the major targets for cholesterol-lowering therapy. The importance of cholesterol reduction in patients with overtly manifest coronary artery disease cannot be overstated, since virtually every major epidemiological study performed to date has shown a significant correlation between the level of serum cholesterol at the time of entry and the risk of subsequent coronary disease. For example, see J. C. Rosa, Circulation, 81, 1721 (1990).
The results of 22 randomized cholesterol-lowering clinical trials to reduce the risk of coronary heart disease indicate an average reduction of 23 percent in the risk of non-fatal myocardial infarction and cardiac death in treated compared with control patients. In particular, a 10 percent decrease in the cholesterol level was associated with a reduction of approximately 20 percent in the incidence of new coronary events (S. Yusef et al., JAMA, 260, 2259 (1988)).
Present therapeutic guidelines include the recommendation that cholesterol-lowering drugs should be considered when cholesterol and low density lipoprotein-cholesterol (LDL-C) levels remain significantly elevated after six months of appropriate dietary therapy. For example, see "National Education Programs Working Group Report on the Management of Patients With Hypertension and High Blood Cholesterol," Ann. of Intern. Med., 114, 224 (1991).
Niacin is commonly employed to treat hypercholesterolemia because it lowers total serum cholesterol, low density lipoproteins (LDL) and triglycerides, and the attendant risk of cardiovascular disease. In addition, recent observations have shown that niacin is effective to increase low levels of high density lipoproteins (HDL).
Niacin is nicotinic acid (pyridine-3-carboxylic acid). It inhibits lipoprotein synthesis by preventing the secretion of very low density lipoprotein (VLDL) from the liver. Because VLDL is a precursor for the intermediate density lipoproteins (IDL) and LDL, the circulating levels of all of the atherogenic lipoprotein fractions are decreased. In addition, niacin decreases levels of lipoprotein a, which has been associated with a two-fold increase in the relative risk of coronary artery disease. The rate-limiting enzyme in cholesterol biosynthesis is hepatic hydroxymethylglutaryl coenzyme A reductase (HMG-CoA reductase). For example, I. Bjorkhem et al., in J. Lipid Res., 28, 1137 (1987) reported high correlations between the relative concentrations of cholesterol precursors such as free lanosterol and lathostenol, cholesterol synthesis and the activity of HMG-CoA reductase.
A wide variety of niacin preparations are available from different manufacturers, each having unique bioavailability, pharmokinetic, and safety profiles. In general, lower doses of niacin (1-3 g/day) are used, because they maintain beneficial lipid effects while minimizing adverse side affects. For example, niacin causes prostaglandin-mediated vasodilation, leading to flushing, warm skin, itching rash and tingling. Aspirin is effective in some cases to control these effects, as is gradual dosage escalation. High niacin (4.3 g/day) also causes substantial incidences of gastrointestinal effects, such as constipation, nausea and heartburn.
Although the vasodilatory and gastrointestinal effects of niacin can either be modulated or are absent at dosage levels which are still effective to lower cholesterol, abnormalities in liver function tests have been observed in 19% of patients treated with daily doses of 2.0 g or less of niacin. (J. D. Alderman et al., Am. J. Cardiol., 64, 725 (1989)). For example, serum transaminase can increase to levels at which niacin must be discontinued. Niacin has also produced hepatocellular degeneration and necrosis. The precise mechanism of injury is not known. However, a dose-relationship suggests some intrinsic hepatotoxic potential that is modified by individual patient susceptibility. See, H. J. Zimmerman, in Hepatotoxicity, Appleton-Century-Crofts; New York, N.Y. (1978) at pages 510-512.
Therefore, a need exists for a method to administer niacin in doses effective to lower serum lipids, while minimizing or eliminating such dose-limiting side effects.